NKR-CAR Receptor Design for Specific Antigen Recognition
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Solution Overview
Problem
Current chimeric antigen receptors (CARs) for T cells, particularly those used in cancer therapy, face limitations such as antigen-independent proliferation and off-target effects due to signaling defects, which can lead to reduced long-term survival and increased risk of harming normal tissues.
Innovation Solution
Development of natural killer cell immune function receptor-chimeric antigen receptors (NKR-CARs) that include specific extracellular antigen binding domains, transmembrane domains, and cytoplasmic domains, such as KIR-CARs, NCR-CARs, SLAMF-CARs, FcR-CARs, and Ly49-CARs, designed to improve signaling and specificity, potentially reducing off-target activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If chimeric antigen receptors (CARs) are used for T cell therapy, then antigen recognition capability is improved, but off-target effects and signaling defects occur
Solution Approach 1:
The patent segments the CAR structure into distinct functional domains: extracellular antigen-binding domain, transmembrane domain, and intracellular signaling domain. By separating these functions and optimizing each independently, the invention achieves better antigen specificity while reducing off-target effects through controlled signal transduction.
Solution Approach 2:
The invention creates composite receptor structures by combining antibody-derived antigen-binding domains (scFv) with T cell receptor signaling components (CD3-zeta chain) and costimulatory signals (CD137, CD28). This composite design enables precise antigen recognition coupled with regulated signaling to minimize off-target activity.
2Productivity
If CARs are engineered for enhanced proliferation, then tumor cell killing capability is improved, but long-term survival of CART cells is reduced
Solution Approach 1:
The patent introduces dynamic regulation to CAR signaling by incorporating costimulatory domains (CD137, CD28) that modulate T cell activation states. This dynamic signaling control allows enhanced proliferation during tumor engagement while preserving long-term cell survival through regulated feedback mechanisms, preventing exhaustion.
3Adaptability or versatility
If artificial receptors are used to bypass MHC constraints, then antigen specificity is improved, but signal transduction defects occur
Solution Approach 1:
The patent uses the CD3-zeta chain as an intermediary component that bridges the artificial antibody-derived antigen-binding domain with the natural T cell signaling machinery. This intermediary ensures that MHC-independent antigen recognition is coupled with reliable, physiologically appropriate signal transduction, maintaining signaling accuracy despite the artificial nature of the receptor.
Data Source
AI summary
The present invention provides compositions and methods for regulating the specificity and activity of immune effector cells for use in immunotherapy. In one embodiment, the invention provides a type of chimeric antigen receptor (CAR) wherein the CAR is termed a “NKR-CAR” which is a CAR design comprising a component of a receptor naturally found on natural killer (NK) cells. In one embodiment, the NK receptor includes but is not limited to a naturally occurring activating and inhibitory receptor of NK cells known as a killer cell immunoglobulin-like receptor (KIR).